A requirement for cellular inflow of nutrients, outflow of waste products, and gas exchange in most tissues and organs is the establishment of a vascular supply. Several processes for blood vessel development and differentiation have been identified. One such process is termed “vasculogenesis” and takes place in the embryo. This process consists of the in situ differentiation of mesenchymal cells into hemoangioblasts, which are the precursors of both endothelial cells and blood cells. “Angiogenesis” is a second such process and involves the formation of new blood vessels from a preexisting endothelium. This process is required for (i) the development of embryonic vasculature, and (ii) a variety of post-natal processes, including, but not limited to, wound healing, tissue regeneration, and organ regeneration. Further, angiogenesis has been identified as a requirement for solid tumor growth and uncontrolled blood cell proliferation.
Vascular Endothelial Growth Factor (VEGF; also designated as vascular permeability factor (VPF) has been identified as a regulator of normal and pathological angiogenesis. VEGF is a secreted growth factor having the following properties (i) an endothelial cell specific mitogen; (ii) angiogenic in vivo and induces vascular permeability; (iii) VEGF expression (and expression of its receptors) has been correlated with vasculogenesis and angiogenesis during embryonic development; and (iv) VEGF is expressed in tumor cells. The VEGF receptor appears to be expressed exclusively in adjacent small blood vessels. VEGF appears to play a crucial role in the vascularization of a wide range of tumors including, but not limited to, breast cancers, ovarian tumors, brain tumors, kidney and bladder carcinomas, adenocarcinomas and malignant gliomas. Tumors have been shown to produce ample amounts of VEGF which stimulates the proliferation and migration of endothelial cells (ECs). This is thought to induce tumor vascularization by a paracrine mechanism.
The angiogenic effect of VEGF appears to be mediated by its binding to high affinity cell surface VEGF receptors (VEGFR).